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GRIN2A and GRIN2B Impacts on Neurological Development and Learning

Updated: Aug 25, 2023


By Viva Voong ‘26

Edited by Evan MacLure ‘26


Despite decades of innovation and discovery, there is still much to discover about the brain, arguably one of the most important organs of the body. One such field for discovery is potential causes for neurodevelopmental disorders experienced by many individuals all over the world. These include seizures, schizophrenia, ADHD, cerebral visual impairment, Alzheimer’s, autism, movement disorders and language disorders. [1] Given that these conditions interfere greatly with aspects of daily lifestyle, related discoveries could benefit many patients who suffer from these disorders. In researching these conditions, many scientists have found a connection to mutations in a specific type of gene in the brain.


GRIN2A and GRIN2B genes are components of specific neurological receptors that relay signals in the central nervous system. [2] When glutamate molecules bind to these receptors, neurons respond by carrying out various chemical signals that in communication with other neurons, can affect physiological conditions in the brain. [3]


Disruptions in the function of receptors can lead to detrimental biological effects. When GRIN2A and GRIN2B genes are over transcribed, receptors can relay signals at a fast rate, leading to overexcitation. On the other hand, if the gene is under-transcribed, receptors struggle to relay signals, which causes inadequate excitation. Both overexcitation and inadequate excitation can lead to neurological conditions. [2]


An example of overexcitation of the GRIN gene was shown in a 26-year-old patient who displayed a history of seizures of varying severity. Upon exploring his family history, researchers discovered that the patient’s father, paternal aunt, and cousin also experienced frequent seizures and suffered from behavioral problems. Researchers looked closer at genes that may be affected in this family and discovered deletions in the GRIN2a gene, which is associated with intellectual disability and epilepsy. [4]


Inadequate gene activation results in susceptibility to development and learning problems. A 4-year-old study subject displayed intellectual disability and some seizures. Upon further inspection of genetic factors that may have contributed to his neurological disorder, researchers discovered a premature stop codon, a specific sequence of genetic material that signals for transcription of the gene, in the GRIN2A gene. His mother and grandmother also displayed the same mutation and had a mild history of seizures during childhood. [4]


A 3-year-old female patient displayed severe developmental delay. Despite the absence of common mutations in patients affected by developmental disorders, the patient had a single lysine amino acid substituted for an asparagine. Asparagine is polar, while lysine is basic and charged. Though seemingly a small mistake, the differing properties of these two amino acids led to changes in channel conformation and interaction with magnesium ion blocks. [4]


The GRIN2A and GRIN2B genes are expressed in many regions of the brain including CA1, CA2, CA3, and the dentate gyrus. These components of the brain are responsible for essential roles in location traction, cognition facilitation, spatial navigation and memory formation. These four regions further project neural signals to other parts of the brain, causing widespread effects on various brain functions. For example, excitation of this gene causes increased activity in associated regions receiving projection. Meanwhile, inhibition of this gene leads to decreased activity in these regions. [5]


By studying specific genes in patients affected by neurological disorders, neuroscientists can diagnose conditions with better precision and develop more accurate treatments tailored to individual patients.


Sources:

  1. ‌GRIN2B gene: MedlinePlus Genetics [Internet]. medlineplus.gov. [cited 2023 Apr 10]. Available from: https://medlineplus.gov/genetics/gene/grin2b/

  2. About GRIN2B [Internet]. GRIN2B Foundation. [cited 2023 Apr 10]. Available from: http://grin2b.com/about-grin2b/

  3. ‌Philadelphia TCH of. GRIN2B-Related Disorders [Internet]. www.chop.edu. 2020. Available from: https://www.chop.edu/conditions-diseases/grin2b-related-disorders

  4. Myers SJ, Yuan H, Kang JQ, Tan FCK, Traynelis SF, Low CM. Distinct roles of GRIN2A and GRIN2B variants in neurological conditions [Internet]. f1000research.com. 2019 [cited 2023 Apr 10]. Available from: https://f1000research.com/articles/8-1940/v1

  5. Endele S, Rosenberger G, Geider K, Popp B, Tamer C, Stefanova I, et al. Mutations in GRIN2A and GRIN2B encoding regulatory subunits of NMDA receptors cause variable neurodevelopmental phenotypes. Nature Genetics. 2010 Oct 3;42(11):1021–6. Available from: https://www.nature.com/articles/ng.677

  6. Fernández-Rúa JM. Mapa del colesterol cerebral y enfermedades neurodegenerativas [image on the Internet]. Biotech Magazine and News. 2020 June 3 [cited 2023 Aug 25]. Available from: https://biotechmagazineandnews.com/mapa-del-colesterol-cerebral-y-enfermedades-neurodegenerativas/


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